Arsenic trioxide-induced apoptosis in H9c2 cardiomyocytes: Implications in cardiotoxicity

Arsenic trioxide (As2O3) achieved dramatic remissions in patients with acute promyelocytic leukaemia. Clinical reports have shown that treatment was associated with cardiotoxicity. We investigated the toxic mechanisms of As2O3 in H9c2 cardiomyocytes. Clinically relevant concentrations of As2O3 (2-10 mu M) reduced the viability of H9c2 cells in a concentration-dependent manner. The decreased cell viability was because As2O3 induced cell apoptosis (cell shrinkage, nuclear alterations and caspase-3 activation), or even necrosis at higher concentrations. Inhibition of caspase-3 with a specific inhibitor, Ac-DEVD-CHO, suppressed apoptosis induced by As2O3. In addition, reactive oxygen species formation and cellular Ca2+ overload were observed in H9c2 cells exposed to As2O3, which was partly inhibited by vitamin E and verapamil. These results suggest that As2O3-induced cardiotoxicity is mediated, at least in part, by activation of caspase-3 pathway, which may be triggered by reactive oxygen species formation and intracellular Ca2+ overload.